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Novel, Existing Biomarkers Advance Targeted Breast Cancer Care


Given the heterogeneous nature of breast cancer, biomarkers evaluated throughout treatment help provide a clearer picture of the treatment paradigm.

Given the heterogeneous nature of cancer, biomarkers evaluated throughout treatment help provide a clearer picture of the treatment paradigm and disease progression, thereby facilitating optimal oncology care. For breast cancer, diagnostic tissue, histologic, prognostic, and predictive biomarkers—both standard and investigative—enable individualized treatment and maximum patient benefit.

A new review published in Virchows Archiv explores a variety of these biomarkers, focusing on recent updates and testing guidance from the College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) for estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) cancers.

“In breast cancer, the last several decades have seen an evolution from providing basic tissue diagnosis to include a comprehensive list of not only histologic biomarkers but protein-expression–based and molecular prognostic and predictive biomarkers,” the authors explained.

With new data indicating that low ER–expressing cancers may have different characteristics than high ER–expressing cancers—since the 2010 CAP/ASCO guidance on ER and HER2 receptors—the new guidance officially acknowledges ER-positive carcinoma with low ER expression as a category of invasive breast cancer. The cancer has gene expression profiles and clinical course profiles similar to ER-negative cancers.

In addition, because some features of ER low–positive cancers may indicate aggressive biology, such as with ER-negative cancers, the new guidance recommends including a standardized comment if reporting on low ER cancers. Doing so, the authors note, “opens the door for other aspects of treatment to be tailored to those considered appropriate for ER-negative cancers.”

Labs are also encouraged to create standard operating procedures to reconfirm ER-low results since this type of cancer is still a rare occurrence, and testing for ER status among patients with ductal carcinoma in situ (DCIS) is now recommended following the NSABP B-24 trial showing that patients with ER-positive DCIS treated with lumpectomy, radiation, and tamoxifen have a lower risk of invasive carcinoma.

The newest guidance also discusses fine-tuning HER2 testing by encouraging standardizing and reporting on results. This stems from previous updates to HER2 testing guidance from 2013 and 2018 that addressed discordant HR testing results seen between central and local labs in several HER2 treatment trials, as well as HER2 heterogeneity and the potential of HER2-low and HER2-mutated cancers to change testing for HER2 status.

Additional guidance updates include the following:

  • For early-stage ER-positive/HER2-negative disease, multigene expression panels have been designated the new standard biomarker for chemotherapy decisions in the presence of endocrine therapy.
  • For ER-negative/HER2-positive/triple-negative early-stage disease, incomplete response to neoadjuvant therapy is now used to indicate need for additional treatment.
  • For decisions on adding a cycle cell inhibitor (abemaciclib) to endocrine therapy, Ki67 has high utilization as an identifier of the highest-risk ER-positive and HER2-negative cancers.
  • When deciding on additional treatment for metastatic disease, recommendations include the following predictive biomarkers:
    • Germline BRCA mutation testing for PARP inhibitor therapy appropriateness in all metastatic disease
    • Programmed death ligand 1 testing for immunotherapy appropriateness in triple-negative disease
    • PIK3CA mutation testing for PI3K inhibitor therapy appropriateness in ER-positive metastatic disease
    • Microsatellite instability, mismatch repair, tumor mutational burden, neurotrophic tyrosine receptor kinase, and comprehensive genomic profiling to identify uncommon targets for targeted treatment

“Existing biomarkers in breast cancer will continue to be fine-tuned and change with evolving treatment options and clinical data,” the authors determined. “In addition, new biomarkers will continue to emerge—likely both as companion diagnostics to new therapeutics and in novel forms such as artificial intelligence analysis, digital pathology, and liquid biopsy samples.”

Their findings also place a spotlight on the increasingly important role pathologists have in deciphering tissue and cancer characteristics in the face of decisions on targeted treatment for breast cancer.


Najjar S, Allison KH. Updates on breast biomarkers. Virchows Arch. Published online January 14, 2022. doi:10.1007/s00428-022-03267-x

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